APPLICANT?S DESCRIPTION Colorectal cancer remains the second leading cause of malignant death, and better preventive strategies are needed. Stool testing, unlike other conventional screening approaches, is noninvasive and requires no cathartic preparation. However, widely-used fecal blood tests yield frequent false-negative and false-positive results that lower the screening effectiveness and raise program costs. There is a compelling biological rationale to target altered DNA exfoliated from neoplasms into stool, and multiple DNA markers would need to be targeted due to the genetic heterogeneity of colorectal neoplasia. Preliminary data suggest that a prototype multi-target DNA-based assay system has potential to detect screen-relevant colorectal neoplasia (early-stage cancer and advanced adenomas) with substantially higher sensitivity and specificity than that of fecal blood tests. The overall objective of this application is to prospectively assess the fecal DNA-based test as a promising new approach to the general screen-detection of colorectal neoplasia. A 3-year cross-sectional multicenter study is planned to compare the validity of the DNA-based test and the most commonly used fecal blood test (Hemoccult) for identification of screen-relevant colorectal neoplasia in 2900 demographically representative average-risk persons using colonoscopy as a gold standard. The performance of the DNA-based test will also be compared to a surrogate for flexible sigmoidoscopy (distal 60 cm of colonoscopy) and to the combination of sigmoidoscopy + Hemoccult. The design will further allow an assessment of the impact of dietary, medication, demographic, and other covariates on test outcomes. Assays will be performed blindly at central laboratories. A specimen bank will be maintained as an important resource for the economical evaluation of additional markers. A state-of-the-art web-based data management system will be employed to efficiently enter and transfer data across the six participating centers with the highest quality control. If the DNA-based test proves to have greater screening accuracy than fecal blood testing, this could translate into more effective cancer control and more efficient use of our limited health care resources.